Tumors, stenoses of biological conduits, and other proliferative tissue can be effectively treated with radiation, which is known to inhibit cellular proliferation. The mechanism by which radiation prevents such proliferative cellular response is by preventing replication and migration of cells and by inducing programmed cell death (apoptosis).
Cells are variably susceptible to radiation, dependent on the types of cells and their proliferative status. Rapidly proliferating cells are generally more radiation-sensitive, whereas quiescent cells are more radiation-tolerant. High doses of radiation can kill all functions of even quiescent cells. Lower levels can merely lead to division delays, but the desirable effect of reproductive death is still obtained. In this case, the cell remains structurally intact but has lost its ability to proliferate, or divide indefinitely.
Traditional high-dose external beam radiation treatment, and prolonged low dose rate, close-distance radiation treatment (brachytherapy), are well-established therapies for the treatment of cancer, a malignant form of cellular proliferation. In particular, attention is currently being directed to the practical aspects of the use of brachytherapy. These aspects are, of course, particularly significant when radioactivity is involved. A disease site in a patient may be exposed to radiation from an external beam, either as a stand-alone procedure or in conjunction with an operative procedure. Alternatively, the radioactivity may be incorporated into an implantable device. In the first case, a higher energy radiation source is used to achieve the necessary penetration of radiation into the tissue to be treated. As a result, other organs or tissue may be unnecessarily exposed to radiation, and safety, handling and logistics problems arise. In the second case, the implantable devices may be quite expensive. In particular, if radioactivity is added to the device, the device may only be effective for radiotherapy during a relatively short period during which the radioactivity is provided at a useful (therapeutic) level. Depending on the radioisotope used, the decay time may be as short as hours, days or weeks.
The current state of the art brachytherapy for treatment of localized lesions such as tumors of, for example, the prostate, breast, brain, eye, liver, or spleen, employs radioactive, "sealed source" seeds. The term "sealed source", as used herein, means that radioisotopes incorporated into a device are integral with the device and cannot be dislodged or released from the host material of the device in the environment of usage. A typical sealed source seed includes a radiation source encapsulated within an impermeable, biocompatible capsule made of, for example, titanium, which is designed to prevent any leaching or release of the radioisotope. The seeds are approximately the size of a grain of rice (typically 0.81 mm in diameter by 4.5 mm long) and are implanted individually at a treatment site within and/or around a lesion, typically with a medium bore (18-gauge) delivery needle.
Disadvantages of the use of such seeds as radiotherapy devices include their nature as discrete, or point, sources of radiation, and the corresponding discrete nature of the dosages which they provide. In order to provide an effective radiation dose over an elongated or wide target area, the seeds should be uniformly and relatively closely spaced. The need to ensure accurate and precise placement of numerous individual radiation sources undesirably prolongs the surgical procedure, and hence the exposure of the surgical team to radiation. Moreover, the use of discrete seeds requires an elaborate grid matrix for their proper placement. This requirement is labor-intensive, and therefore costly. In addition, the discrete nature of the seeds renders them more susceptible to migration from their intended locations, thereby subjecting portions of the lesion, the treatment site, and surrounding healthy tissue to over- or under-dosage, reducing the effectiveness and reliability of the therapy.
Other disadvantages exist in radioactive seed therapy. Relatively few radionuclides are suitable for use in sealed-source seeds, because of limited availability of radioisotopes with the necessary combination of half-life, specific activity, penetration depth and activity, and geometry. In addition, the implantation of seeds generally requires a delivery needle with a sufficiently large bore to accommodate the seeds and may, in some cases, require an additional tubular delivery device. The use of a relatively large delivery needle during seeding may cause unnecessary trauma to the patient and displacement of the lesion during the procedure. Also, because of the risk of migration or dislodgement of the seeds, there is the risk that healthy tissues near or remote from the lesion site will be exposed to radiation from seeds which have become dislodged from their intended locations and possibly carried from the body within urine or other fluids. In addition, radioactive seed therapy is inadequate for treating certain types of intraluminal tissue proliferation, such as, for example, stenosed coronary arteries, and therefore a need exists for more suitable radiotherapy devices for such intraluminal brachytherapy applications.
Radiotherapy devices made of palladium-103 are desirable because palladium-103 has a half life of about 17 days and a photon energy of 20.1-23 KeV, which makes it particularly suitable for use in the treatment of localized lesions of the breast, prostate, liver, spleen, lung and other organs and tissues. Because palladium-103 is unstable and not naturally occurring in the environment, it must be manufactured, generally either by neutron activation of a palladium-102 target, or by proton activation of a rhodium target. In the neutron activation process, a palladium-102 isotope is exposed to a neutron flux in a nuclear reactor to convert palladium-102 to palladium-103. The extent of the conversion is dependent on the neutron flux and the duration of the bombardment in the reactor. The palladium-103 thus formed is fabricated into radioactive seeds. This approach is disclosed in, for example, U.S. Pat. No. 4,702,228 to Russell, Jr. et al.
The neutron activation approach for the transmutation of Pd-102 to Pd-103 can be prohibitively expensive, as the natural abundance of palladium-102 is less than one percent. Enrichment of this isotope to even 20% levels is very costly. In addition, the utility of this process is unsatisfactory, as other isotopes of palladium and other elements, as well as impurities, may be formed and/or activated in the process and can alter or otherwise interfere with the desired radiation, unless further purification is performed.
In the proton activation process, a rhodium-103 target is provided which is irradiated with a proton beam to transform a portion of the rhodium to palladium-103. This process requires that the rhodium-103 target be cooled and then irradiated until a sufficient amount of palladium-103 is obtained to enable chemical separation of the palladium from the rhodium. The rhodium target is then immersed in a strong solvent to separate palladium-103 from rhodium-103. The palladium-103 radionuclides can now be used directly or formed into compounds for later use. This material is generally absorbed into or otherwise incorporated into a non-radioactive carrier material which is then placed into a non-radioactive secondary container, such as a titanium can or shell, and sealed to form a radioactive seed. The secondary container may include some type of radiopaque marker to allow it to be radiographically visible. This approach is disclosed in, for example, U.S. Pat. No. 5,405,309 to Carden, Jr.
The proton activation approach also has disadvantages. The process requires wet chemistry separation to isolate palladium-103 from rhodium-103, and this and other necessary steps have associated yield losses. The disadvantages of discrete seeds in brachytherapy applications have already been discussed.
U.S. Pat. No. 5,342,283 to Good discloses multi-layer radioactive microspheres and wires which are made by forming concentric radioactive and other coatings on a substrate. The radioactive coatings are made by various deposition processes, including ion plating and sputter deposition processes, as well as via exposure of an isotope precursor, such as palladium-102, to neutron flux in a nuclear reactor. The radioactive wires may have nonuniform distributions of radioactivity over their surfaces, as needed for a particular treatment.
A disadvantage of the Good radioactive devices is that they cannot be made economically or simply. As previously mentioned in connection with the creation of palladium-103 from palladium-102 using neutron flux, such processes are prohibitively expensive and require lengthy and costly wet chemistry separation steps to isolate the radioactive isotope from the non-radioactive precursor. Further, the coating methods disclosed by Good for making radioactive coatings are relatively complicated, multistep processes which are difficult to control. In addition, the multiple coatings of the Good devices may detach, deteriorate, flake, spall, peel, leach or otherwise degrade with time and/or exposure to bodily fluids, resulting in dissemination of radioactive and other materials into the body, with potentially harmful consequences.
A relatively recent article by Eigler et al. (circa 1996) discloses methods of proton activation of a nickel-titanium stent for use in intracoronary brachytherapy applications to produce a vanadium-48 radioisotope on the surface of the stent via transmutation. This approach at least eliminates the cumbersome wet chemistry processes of the prior art proton activation processes; however, it too has its deficiencies.
It would therefore be an advancement in the art to provide a general purpose radiotherapy device which can be relatively easily and economically fabricated.